Isolation and purification of carboxylic acids are important industrial processes that can be quite difficult to accomplish when such carboxylic acids are prepared in complex mixtures such as, for instance, fermentation broths. Well-known examples of such fermentatively prepared carboxylic acids are the classes of β-lactams such as for example clavulanic acid, penicillin G and penicillin V, statins such as for example compactin, lovastatin, mevastatin, pravastatin and simvastatin, (poly-)unsaturated fatty acids such as for example arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, linoleic acid, linolenic acid and retinoic acid and other molecules of industrial relevance such as for example biotin, cholic acid, enteromycin, fusidic acid, helvolic acid, jasmonic acid, lactobacillic acid, laidlomycin, mycophenolic acid, pimaric acid, prostaglandin, rifamycin B, shikimic acid and the like.
The processes for the isolation and purification of these carboxylic acids known from patent and technical literature include different combinations of extraction, chromatography and crystallization methods. Some of them additionally include isolation and purification via different salts.
For example, in U.S. Pat. Nos. 4,342,767 and 4,319,039, the ammonium salt of lovastatin is isolated from an organic phase which has been extracted from the fermentation medium. Also disclosed are salts of lovastatin with ethylene diamine, tetramethylammonia, N-methylglucamine, L-lysine, L-arginine and L-ornithine. In EP 65,835 various salts of tetrahydro-M-4 or tetrahydro-isoM-4 (wherein M-4 denotes a specific HMG-CoA reductase inhibitor) are suggested, such as salts with octyl amine, 2-ethylhexyl amine, benzyl amine, α-methyl-benzyl amine, phenethyl amine, dibenzyl amine, N-methylbenzyl amine, N,N-dimethylbenzyl amine, N,N-diethylbenzyl amine, N-ethyl-N-methylbenzyl amine, tribenzyl amine, cyclopentyl amine, cyclohexyl amine cycloheptyl amine, N-methylcyclopentyl amine, N-ethylcyclohexyl amine, N-ethylcycloheptyl amine, dicyclohexyl amine, N,N-dimethylcyclopentyl amine, N,N-dimethylcyclohexyl amine, N,N-diethylcycloheptyl amine, pyrrolidine, N-methylpyrrolidine, piperidine, N-methylpiperidine and morpholine. GB 2073199 also discloses the preparation of different salts of HMG-CoA reductase inhibitors from the already isolated substance in the lactone form. U.S. Pat. Nos. 5,763,653 and 5,763,646 disclose the preparation of the cyclopropyl amine and n-butyl amine salts of lovastatin. U.S. Pat. No. 6,838,566 describes the formation of salts of atorvastatin, lovastatin, mevastatin, pravastatin and simvastatin with specific amines, namely adamantyl amine, 2-amino-3,3-dimethylbutane, 3-(2-aminoethylamino)-propyl amine, tert-amyl amine, n-butyl amine, sec-butyl amine, tert-butyl amine, cyclobutyl amine, cycloheptyl amine, cyclohexyl amine, cyclopentyl amine, dibutyl amine, dicyclohexyl amine, N,N-diethylcyclohexyl amine, N,N′-diethylene diamine, N,N′-diisopropylethylene diamine, N,N-dimethylcyclohexyl amine, (±)-1,2-dimethylpropyl amine, 1,2-dipiperidinethane, dipiperidinemethane, N-isopropylcyclohexyl amine, N-methylcyclohexyl amine, N-methylethylene diamine, N-methyl-1,3-propane diamine, neopentyl amine, norboryl amine, N,N,N′,N′-tetramethyl-1,4-diaminobutane, N,N,N′,N′-tetramethyl-1,2-diaminoethane and N,N,N′,N′-tetramethyl-1,6-diaminohexane.
Similar approaches are also known for other fermentatively prepared carboxylic acids, such as the β-lecterns. In case of clavulanic acid, the product may be extracted in an organic phase and crystallized as a salt of clavulanic acid with an organic amine, and isolating such an amine salt. In such a process the amine salt is formed as an intermediate in the process of converting crude clavulanic acid into a pharmaceutically acceptable salt. Such a process is described in for example EP 26044, in which a solution of impure clavulanic acid in an organic solvent is contacted with tert-butyl amine to form the tert-butyl amine salt of clavulanic acid, which is then isolated. Other similar processes are known which use other organic amines, such as tert-octyl amine (EP 594099) diethyl amine, tri-(lower alkyl) amines, dimethylaniline and N,N′-diisopropyl-ethylene diamine. WO 93/25557 discloses a very extensive list of amines which can be used in this way. WO 94/22873 discloses use of various tertiary diamines such as N,N,N′,N′-tetramethyl-1,2-diaminoethane, N,N,N′,N′-tetramethyl-1,6-diaminohexane, 1,2-dipiperidinoethane and dipiperidinomethane. WO 96/20199 discloses the use of bis(2-dimethylaminoethyl)ether. GB 2298201 discloses the use of various benzhydryl amines. WO 96/33197 discloses the use of further amines including symmetrical N,N′-alkylethylene diamines, such as N,N′-diisopropyl-ethylene diamine, N,N′-diethylene diamine, N,N′-dibenzylethylene diamine and N,N,N′,N′-tetramethylene diamine. WO 98/21212 discloses clavulanic acid salts with the amines N,N,N′,N′-tetramethylethylene diamine, 1,3-bis(di-methylamino)-2-propanol, benzhydryl amine and bis(2-(dimethylamino)ethyl)ether. Finally, WO 98/23622 discloses diisopropylethylene diamine clavulanic acid salt.
Also for mycophenolic acid, several amine salts have been described. In WO 04/20426 the dibenzyl amine, ammonium and dicyclohexyl amine salts have been described and in Aust. J. Chem. (1978), 31, 353-64, the triethyl amine salt is described.
Indeed many amine salts of fermentatively prepared carboxylic acids have been described. Nevertheless, in industry there exists a constant need for rationalization of the production and shortening of the production processes as well as for the use of inexpensive starting materials. Therefore, there is a constant need for alternative salts of carboxylic acids, preferably with properties similar or improved compared to those described in the art.